Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.2.0
• GENE/GENE PANEL: COL3A1
• Condition: Ehlers-Danlos Syndrome Type IV
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• COL3A1 ⇔ 130050 (ehlers-danlos syndrome, vascular type; edsvasc): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: COL3A1 ⇔ (OMIM:130050)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Vascular or organ rupture or perforation / Avoidance of invasive procedures	3	3C	2A	2	10CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

There are no good current estimates of the prevalence of Ehlers-Danlos Syndrome (EDS) type IV in any population because a large proportion of cases remain undiagnosed. A minimum prevalence of about 1:200,000 can be estimated by extrapolating from the number of known individuals with genetic testing, biochemical, or pedigree-confirmed diagnoses in the United States.
EDS type IV appears to constitute approximately 5-10% of all EDS cases. [1, 2, 3, 4]

Clinical Features

EDS type IV, or vascular EDS, is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have EDS type IV. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously.
The vascular complications may affect all anatomical areas; spontaneous rupture of the aorta and medium-to-large size vessels are the most frequent complications reported. There is also a high risk of recurrent perforation in the sigmoid colon. [1, 2, 3, 4, 5, 6, 7]

Natural History

The overall mortality of EDS type IV is 90% by the age of 50 because of spontaneous rupture of vessels and internal organs.
The median survival for individuals with EDS type IV is 48 years.
Vascular fragility is dominant in the third and fourth decade.
Pregnancy increases the likelihood of a uterine or vascular rupture. Pregnancy for women with EDS type IV confers as much as a 12% risk for death from peripartum arterial rupture or uterine rupture. [1, 2, 3, 7]

2. How effective are interventions for preventing harm?

Patient Management

Information on the effectiveness of the patient management recommendation(s) below was not provided.
Currently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made. (Tier 4) [1]

Invasive procedures (treatment, diagnostic, etc.) should be avoided, except in life-threatening situations. (Tier 1) [2]

Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain. (Tier 4) [1]

Educating pregnant women with EDS type IV as to possible complications, and frequent surveillance in a high-risk obstetrical program is recommended. Pregnancy for women with EDS type IV has as much as a 12% risk for death from peripartum arterial or uterine rupture. (Tier 4) [1]

A MedicAlert bracelet should be worn. (Tier 4) [1]

Surveillance

There are no published data that assess the efficacy of screening strategies to identify the regions in the arterial vasculature at highest risk. [1]

Circumstances to Avoid

Individuals with EDS type IV should not engage in any competitive athletic activity. (Tier 2) [2, 6]

Unless the procedure is considered absolutely life-saving, surgery and all other invasive procedures should be avoided whenever possible. (Tier 1) [2]

Examples of invasive procedures:
- Diagnostic colonoscopy should not be performed in patients with EDS type IV. (Tier 1) [2]

- Arteriograms are not recommended. (Tier 3) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of individuals with mutations in COL3A1 is estimated to range from 1:50,000 to 1:200,000. (Tier 4) [1]

Penetrance

Penetrance appears to be close to 100% with missense or exon-skipping mutations; the age at which the mutation becomes penetrant may vary (Tier 4) [1]

Relative Risk

NA

Expressivity

There is high variability in disease expression, highlighted by the fact that clinical diagnosis is based on any two of four possible major diagnostic criteria, and that two or more of thirteen possible minor diagnostic criteria are supportive but not sufficient for diagnosis. (Tier 4) [1]

A subpopulation of individuals with EDS type IV (3-4%) have haploinsufficiency mutations; improved outcomes are reported in this group, including a 15-year delay in onset of complications, similarly improved life expectancy, and paucity of both obstetric and bowel complications. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Management could result in significant alterations to lifestyle choices (pregnancy, participation in sports) and medical treatment/screening

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Because many families with EDS type IV are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with a mild phenotype do not come to medical attention and, therefore, go undetected (Tier 4) [1]

Date of Search: 07.01.2014

Reference List

1. MG Pepin, ML Murray, PH Byers. Vascular Ehlers-Danlos Syndrome. 1999 Sep 02 [Updated 2015 Nov 19]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1494

2. Burcharth J, Rosenberg J. Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. Dig Surg. (2012) 29(4):349-57.

3. Ehlers-Danlos syndrome, vascular type. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=286

4. Bergqvist D, Bjorck M, Wanhainen A. Treatment of vascular Ehlers-Danlos syndrome: a systematic review. Ann Surg. (2013) 258(2):257-61.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT. MIM: 130050: 2016 Jul 09. World Wide Web URL: http://omim.org.

6. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol. (2005) 45(8):1340-5.

7. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J Am Coll Cardiol. (2010) 55(14):e27-e129.